Inflammation has become a well-recognized component of most neurodegenerative disorders, including Alzheimer's disease (AD). Until recently, we did not have the tools to reliably separate resident brain microglia from peripheral myeloid cells to delineate their functions in the brain. In this proposal, we will characterize different myeloid cell populations, such as resident brain microglia and peripheral monocytes, using elegant single-cell next-generation RNA sequencing (scRNA-Seq). We will determine the response of these neural immune components to physiological brain activity and neurodegeneration. Using novel models of mice with conditional targeting, we will manipulate AD risk genes specifically in brain microglia, and characterize the consequences, at both the single-cell and whole-animal level, in wildtype mice and mouse models of AD-like pathology. Importantly, we will compare these gene expression profiles to those obtained from over 500 well- studied healthy individuals and AD patients to assess the relevance of different monocyte phenotypes to the onset and progression of human AD.